ES2829644T3 - Flavor Masked Oral Pharmaceutical Composition - Google Patents

Abstract

An immediate release particle comprising a core and a cladding, wherein the core comprises an agglomerated active ingredient in an amount of at least 10% by weight relative to the weight of the core, and wherein the cladding basically consists of 70 to 90% by weight of a triglyceride and 10 to 30% by weight of a polysorbate, and wherein the lower limit of the triglyceride melting range is greater than 20 ° C, and wherein the coating weight is 20 to 70 % by weight relative to the total weight of the coated particle.

Description

DESCRIPTION

Flavor Masked Oral Pharmaceutical Composition

Field of the invention

The present invention relates to the field of pharmaceutical products, and relates to oral pharmaceutical formulations, their manufacture and their use.

Background of the invention

Most patients prefer to take orally administered medications over other routes of administration. However, to be acceptable to patients, an oral drug product must be easily swallowed and without an unpleasant or bitter taste, or other undesirable organoleptic properties.

Many drug substances, also commonly referred to as active pharmaceutical ingredients (APIs), exhibit a rather bad taste. A bad taste often means a significant level of bitterness, but it can also involve other unpleasant sensations, such as a burning, stinging, metallic, or astringent mouthfeel.

Although taste masking is generally quite easy to achieve with a conventional tablet that can be coated with a suitable polymeric coating, and also in the case of a capsule formulation in which the capsule shell itself provides a barrier that prevents the contact between the active ingredient and the oral mucosa of the patient during administration, it is much more difficult to mask the taste of a compound that tastes bad when formulated as a dispersible, effervescent, or orally disintegrating dosage form or as granules for administration direct oral ("direct-to-mouth granules"), because in these cases the unit dose is not swallowed in its entirety, but rather the formulation comes into substantial contact with the oral mucosa. In the case of effervescent formulations, the Drug is generally dissolved in a larger amount of water, such as 200 mL, and sufficient masking can be achieved in this diluted form. efficient flavor through the incorporation of sweetening agents and flavors. The most difficult from the point of view of taste is the formulation of the active ingredient in pharmaceutical forms whose administration potentially allows the drug to come into contact with the oral mucosa in a concentrated form, as in the case of orally disintegrating tablets or granules. for direct oral administration. On the other hand, such dosage form designs are highly desirable for high dose drugs, due to their excellent ability to be swallowed even without water.

Additional technical difficulties arise when IFA is not easily processable, for example due to sensitivity to heat stress or moisture. Another particular difficulty is the processing of mechanically unstable IFA particles, especially drug particles representing agglomerates or granules. The poor mechanical stability of the IFA particles means that they cannot be easily coated, since the thermal and mechanical stress involved in most coating processes would lead to the shrinkage or disintegration of the agglomerate, which would cause the generation of dust from Undesirable IFA and substantially reduced coating efficiency. As a result, the taste masking effect would not be sufficient, at least not if the IFA is to be incorporated into an oral (direct to mouth) granule formulation or an orally disintegrating tablet.

However, effective taste masking may require providing a coating on the surface of the active ingredient. The coating serves as a physical barrier layer between the active ingredient and the patient's taste buds and olfactory receptors. In addition, a coating can also be useful to protect a sensitive or labile active ingredient during storage.

In principle, the taste masking coatings can be polymeric film coatings or lipid coatings. Polymeric coating systems are sprayed onto the drug cores in the form of aqueous or organic solutions or dispersions. A disadvantage of organic solvents is the need for special equipment and their negative impact on the environment. Aqueous coating systems also consume substantial energy, as polymeric coating material must be heated above its film-forming temperature to bond, and removal of water requires more thorough drying than typical organic solvents. . In addition, many polymeric coating systems show curing effects, that is, their properties change over time, such that the dissolution behavior of the drug can be compromised during storage.

In principle, a lipid coating can be applied to IFA particles by various thermal processing methods, such as melt extrusion, spray coagulation, melt coating in a mixer, or fluidized bed coating.

Lipid coating systems, such as coatings based on waxes like carnauba wax, do not require a solvent to be applied to the drug-containing cores: They can often be used as melts in melt coating processes in hot. On the other hand, these types of coatings, due to the poor water solubility of their main constituents, also tend to have a negative impact. Substantial on drug release profile, especially if rapid drug release is required. For example, Sinchaipanid et al (Powder Technology, 2004, 141,203-209) describe hot melt coatings of granulated propranolol hydrochloride spheres by using a coating consisting of a mixture of Precirol® ATO5, (glyceryl palmitostearate , comprising mainly diglycerides of palmitic and stearic acid) and Gelucire ® 50/02 (saturated polyglycosylated glycerides). Compared to uncoated propranolol spheres, the addition of the coating resulted in a significant decrease in the rate of drug release, which in fact provided a regulated and controlled release of the drug. Thus, in cases where immediate drug release is necessary, wax coatings are often not effective.

The stability of a lipid or waxy taste masking coating over time can also affect the release profile of the active ingredient. The conversion of an initially formed polymorph of a coating excipient into a more thermodynamically stable crystalline form over time during the course of storage, sometimes also caused by exposure to different environmental conditions, can lead to significant and undesirable variations in the dissolution profile of the drug of the composition.

Additionally, hot melt processing conditions can be crucial for temperature sensitive drug compounds. Depending on the type of lipid or waxy coating material, the coating process is sometimes carried out at temperatures greater than 60 ° C, and sometimes also greater than 80 ° C or even 100 ° C. Depending on the type of equipment used, additional disadvantages, such as high shear or pressure, can make the coating process unattractive to certain APIs, particularly mechanically unstable API particles such as agglomerates.

WO 2010/037543 A1 describes the extrusion of lipid spheres for taste masking. The method requires mixing the active ingredient with a mixture of lipids comprising a hard fat and glycerol trimyristate or glycerol distearate, followed by cold extrusion of the mixture and spheronization of the extrudate to obtain spherical spheres or granules. By using a sufficient amount of lipid material, a coating is formed which completely covers the surface of the spheres and is preferably at least 5 µm thick. A major disadvantage, however, is that the release of the incorporated drug substance is substantially slowed, even in the case of an easily water-soluble compound such as sodium benzoate. The inventor reports that even after 45 min dissolution testing at 37 ° C, the drug is not completely released from the formulation.

WO 2008/071407 A2 describes immediate or rapid release spheres comprising cefpodoxime, an antibiotic compound that has a bad taste. The spheres exhibit a taste-masking coating comprising carnauba wax and a hydrogel-forming agent, such as a polymer derivative of cellulose, alginate, or gum. In the document it is mentioned that many lipophilic substances, such as cocoa butter or Precirol®, are prone to polymorphic changes during storage. As structural changes would lead to inconsistencies in dissolution profiles, such compounds are considered unsuitable for use as coating excipients for these spheres. The document therefore teaches the use of waxes such as carnauba wax which have a high melting range and which do not exhibit polymorphic changes.

US 5,891,476 describes acetaminophen particles or granules coated with a non-polymorphic waxy component such as carnauba wax and optionally other lipid components and / or surfactants. According to the document, the use of such waxes eliminates the risk of variable dissolution rates resulting from the change of the morphology of the coating over time and under different conditions.

However, a disadvantage of using waxy components that have a high melting point, such as carnauba wax (melting range of approx. 82 to 86 ° C) in hot melt coatings is that the active ingredient itself also it can be subjected to the higher temperatures necessary to keep the coating components in the molten phase during the coating process. Higher temperatures during processing can increase the degradation of thermolabile active ingredients. Furthermore, hot melt coating processes involving molten carnauba wax are very difficult to handle, because the coating composition must be maintained at even higher temperatures, e.g. ex. at around 100 ° C or higher, and because this wax solidifies very quickly upon cooling, it tends to clog the tubes through which it is pumped into the spray nozzle, as well as the nozzle itself.

WO 2010/070028 A1 describes various flavor masked hot melt coated compositions incorporating the active ingredients acetaminophen, ranitidine, and caffeine. The coatings comprise, as a meltable lipophilic excipient, stearic acid, Precirol ATO 5 (a mixture of mono-, di- and triglycerides of palmitic and stearic acid), or Compritol 888 ATO (glyceryl behenate). The coatings further comprise a release compound, ie, a compound that increases the disintegration of the taste-masking layer in the gastrointestinal fluid, such as by forming pores or holes through swelling (eg Amberlite IRP 88) or the release of carbon dioxide (eg calcium carbonate); and a surfactant or other substance (eg, PEG 3000 or Tween 20) that is incorporated to achieve a homogeneous distribution of the release compound in the meltable lipophilic excipient. However, the resulting coating compositions are quite complex. Due to the insolubility of the release compound in the meltable lipophilic compound, there is a risk of phase separation during the coating process, which leads to poor reproducibility.

Furthermore, since the document does not mention this aspect, it is not clear whether the release profiles achieved with such complex and inherently incompatible coating compositions are stable under storage conditions.

US 2010/0092569 A1 relates to taste masking of conjugated linoleic acid compounds by suspending an adsorbate of the active ingredient on silica powder in a molten lipid matrix, and subsequent spray cooling, so that coated particles are formed. The lipid matrix comprises triglycerides of C16, C18, C20 and C22 saturated fatty acids and 3% by weight of an unidentified emulsifier, the function of which is to ensure a homogeneous dispersion of the active ingredient in the molten lipid. The purpose of the coating is to protect the light and air sensitive linoleic acid compound from degradation. The taste-masked product is used as an additive in animal feed.

However, the preparation of a suspension in the molten state involves the complete exposure of the active ingredient to temperatures above the melting range of the lipid, in the present case about 70 ° C, which may be acceptable in the case of certain active ingredients. or in the case of animal feed, but not for temperature sensitive pharmaceuticals for human use. Furthermore, the document does not mention the resulting dissolution profiles, which do not appear to be relevant in this case.

An object of the invention is to provide an improved method for masking the taste of pharmacological substances that are mechanically unstable, such as agglomerated particles of IFA. Furthermore, an objective is to provide an improved taste-masked form of agglomerated drug particles that are immediate release, that is, that exhibit rapid dissolution of the drug and a stable dissolution profile. It is also an object to provide improved methods and compositions for masking the taste of agglomerated drug particles that are sensitive to heat or humidity. A further object is to provide improved pharmaceutical compositions comprising agglomerated taste-masked drug particles with rapid dissolution of the drug. Yet another object is to provide taste-masked compositions that can be manufactured under mild conditions, as well as processes by which taste-masked compositions of sensitive compounds can be prepared. Furthermore, an objective is to overcome one or more of the limitations or disadvantages associated with the prior art. Other objects will be apparent based on the description and the claims.

These and other objectives are achieved by subject matter as defined in the independent claims below, with particular embodiments outlined in the dependent claims.

Summary of the invention

The invention provides, according to a first aspect, an immediate release particle comprising a core and a cladding. The core comprises an agglomerated active ingredient in an amount of at least about 10% by weight relative to the weight of the core, and the coating basically consists of 70 to 90% by weight of a triglyceride that is solid at room temperature (i.e. , a triglyceride whose lower limit of the melting range is greater than 20 ° C) and from 10 to 30% by weight of a surfactant, specifically a polysorbate. The weight of the coating is 20 to 70% by weight with respect to the total weight of the coated particle. The coated particle enables immediate release, that is, rapid dissolution of the active ingredient in an aqueous medium.

The core may consist of an agglomerated particle, such as a granule or sphere, comprising the active ingredient and one or more pharmaceutical excipients.

The solid triglyceride is preferably a saturated triglyceride. Its three fatty acid chains can be identical, as in trimyristin (or glyceryl trimyristate), trypalmitin (or glyceryl tripalmitate), tristearin (or glyceryl tristearate), triarachidine (or glyceryl triarachidate), or tribehenin (or tribehenyl tribehenate). glyceryl). Tripalmitin and tristearin are among the preferred triglycerides.

The surfactant is a nonionic surfactant, specifically a polysorbate. Polysorbate 65 is one of the preferred surfactants, particularly in combination with a saturated triglyceride selected from tripalmitin and tristearin. The weight ratio of triglyceride to surfactant is in the range of 70:30 to 90:10, in particular in the case of tripalmitin or tristearin and polysorbate 65. The coating basically consists of the triglyceride and the polysorbate.

In a further aspect, the invention provides a method for the preparation of immediate release particles comprising a core with an agglomerated active ingredient in an amount of at least 10% by weight relative to the weight of the core, and a coating with a triglyceride which is solid at room temperature and a surfactant, specifically a polysorbate. The method includes the steps of (a) providing a core particle comprising at least 10% by weight of an agglomerated active ingredient relative to the weight of the core, (b) providing a coating composition consisting basically of 70 to 90 % by weight of a molten triglyceride and 10 to 30% by weight of a surfactant, specifically a polysorbate, and (c) coating the core particle with the coating composition, wherein the coating weight is 20 to 70% by weight relative to the total weight of the coated particle. It is preferably carried out in a fluidized bed coater or in an air flow bed coater. Product temperature can be kept at around 20 to 50 ° C for the coating step (c).

The description not according to the invention also refers to an immediate release particle comprising a core and a coating, wherein the core comprises an agglomerated active ingredient in an amount of at least 10% by weight relative to the weight of the core, and wherein the coating basically consists of a triglyceride that is solid at room temperature and a surfactant, specifically a polysorbate, and said particle can be obtained by a method comprising the steps of (a) providing a core particle comprising a agglomerated active ingredient in an amount of at least 10% by weight relative to the weight of the core, (b) provide a coating composition consisting basically of 70 to 90% by weight of a molten triglyceride and 10 to 30% in weight of a surfactant, specifically a polysorbate, and (c) coating the core particle with the coating composition, wherein the weight of the coating is d 20 to 70% by weight relative to the total weight of the coated particle.

In a further aspect, the invention provides a pharmaceutical composition according to claim 11, comprising immediate release coated particles according to any of claims 1 to 10, comprising a core comprising an agglomerated active ingredient in an amount of at least 10 % by weight relative to the weight of the core and a coating consisting basically of a triglyceride that is solid at room temperature and a polysorbate. The composition can optionally be formulated in the form of granules, such as dispersible granules, effervescent granules, direct-to-mouth granules, or in the form of a tablet, such as a dispersible tablet, an effervescent tablet, or an orally disintegrating tablet.

Detailed description of the invention

In a first aspect, the invention provides an immediate release particle comprising a core and a cladding. The core comprises an agglomerated active ingredient in an amount of at least 10% by weight relative to the weight of the core, and the coating basically consists of 70 to 90% by weight of a triglyceride whose lower limit of the melting range is greater than 20 ° C (ie a triglyceride that is solid at room temperature) and 10 to 30% by weight of a surfactant, specifically a polysorbate. The weight of the coating is 20 to 70% by weight with respect to the total weight of the coated particle.

Solid at room temperature means that the lower limit of the triglyceride melting range is greater than about 20 ° C; and the term "consisting basically" and related terms (eg "consist" and "consists"), as used herein in reference to the coating, means that no additional components other than the coating have been added. of the components named to prepare the coating. However, very small amounts of other materials, such as impurities, may be present.

The particles enable immediate release of the active ingredient in the presence of an aqueous medium. According to the invention, the coated particle has a specific structure, comprising at least one core and at least one coating layer. The core comprises an agglomerated active ingredient, such as a granule or a sphere, which may in turn be composed of primary particles such as crystals. The coated particle is useful as a component of a pharmaceutical composition for oral use.

The core is generally solid, optionally semi-solid, and comprises an agglomerated pharmacologically active ingredient. The agglomerated active ingredient can be crystalline, non-crystalline or partially crystalline. The primary particles of the active ingredient are associated in the form of agglomerates such as spheres, microspheres, granules, or microparticles. The shape of the core, ie the agglomerated active ingredient, depends mainly on the nature, composition and manufacturing method of the core and / or agglomerate material. As used herein, the terms "agglomerate" or "agglomerate" include materials prepared by wet or dry granulation, compaction such as roller compaction, pelletization, or precompression. A granulated active ingredient is also an agglomerated active ingredient. The particle size of the agglomerated active ingredient as determined by sieving (ie, the diameter of the sieve) is generally less than about 2.5 mm, and preferably less than about 1.5 mm. In more preferred embodiments, the core has a diameter in the range of from about 100 to about 1,000 pm, from about 80 to about 600 pm, from about 100 to about 400 pm, or from about 300 to 800 pm, respectively. In some other preferred embodiments, the core particle size is from about 200 to 500 pm, or from about 250 to 750 pm.

Optionally, the core consists substantially of an agglomerated active ingredient. In this context, the term "consists substantially of" means that no additional components have been added to the active ingredient to prepare the core and / or the agglomerate. However, very small amounts of other materials, such as impurities, may be present.

Alternatively, the core may comprise an agglomerated active ingredient that is a composite agglomerated particle, or a formulated agglomerated particle comprising an active ingredient and at least one pharmaceutically acceptable excipient. For example, a granule, bead or microsphere comprising an active ingredient and at least one binder can be used. Commonly known methods can be used to formulate and manufacture such granules, spheres or microspheres. In an especially preferred embodiment, the core comprises a agglomerate of an active ingredient and a binder, such as microcrystalline cellulose.

The core comprises at least about 10% by weight of the active ingredient. In the most preferred embodiments, the core comprises at least about 30% by weight of the active ingredient, or at least about 50% by weight, or at least about 60% by weight, or at least about 70% by weight. , or at least about 80% by weight, or at least about 90% by weight, or at least about 95% by weight, or even at least about 98% by weight of the active ingredient, respectively. These percentages are understood to be relative to the weight of the core. Of course, the core (or even the coating) may further comprise some non-agglomerated active ingredient, as long as the amount of agglomerated active ingredient in the core is at least 10% by weight.

In particular, the core may comprise agglomerates of an active ingredient with undesirable organoleptic properties, such as a bitter, burning, stinging, metallic, or astringent mouthfeel, when administered orally, and requiring taste masking. The active ingredient can be selected, for example, from analgesics, non-steroidal anti-inflammatory drugs, proton pump inhibitors, antitussives, antihistamines, stimulants, sedatives, decongestants, antiemetics, phosphate binding agents, and sympathomimetics.

Preferred active ingredients include ibuprofen, paracetamol, caffeine, calcium acetate, aspirin, pseudoephedrine, dimenhydrinate, omeprazole, pantoprazole, or lansoprazole, or any of their salts, isomers, polymorphs, and hydrates.

In one especially preferred embodiment, the active ingredient is agglomerated ibuprofen, or an agglomerated ibuprofen salt, in particular agglomerated ibuprofen sodium or potassium ibuprofen. According to another preferred embodiment, the invention provides an immediate release particle comprising a core and a coating, wherein the core comprises agglomerated ibuprofen, potassium ibuprofen or sodium ibuprofen (eg dihydrate), and wherein the coating comprises a triglyceride which is solid at room temperature and a surfactant. The cladding is understood to be a layer, or several layers, of material that substantially encloses the core, or at least the majority of the surface of the core. As an important object of the invention is to provide effective masking of the taste of the active ingredient, it is preferred that at least 80% of the surface, or at least 90% of the surface, or at least 95% of the surface, or substantially the entire surface of the core is covered with the cladding. At the same time, a person skilled in pharmaceuticals will appreciate that a bulk material comprising multiple particles according to the invention may include a minor fraction of particles whose coatings may not completely or substantially cover the cores, even though most of the particles exhibit coatings. substantially complete.

The coating of the invention comprises at least one triglyceride that is solid at room temperature and a surfactant, specifically a polysorbate. As used herein, a triglyceride is an ester derived from glycerol and three fatty acids. A triglyceride can also be called a triacylglyceride, or a fat. The composition of the coating is of key importance to the invention.

Agglomerated particles often have uneven, uneven surfaces, which can also be porous. Therefore, efficient application of an effective coating layer is normally difficult. This has particular consequences for agglomerated particles comprising active ingredients that require taste masking. It has been discovered that a coating composition comprising, or consisting essentially of, a triglyceride that is solid at room temperature (eg with a melting range> 20 ° C) and a surfactant, such as a polysorbate, is especially suitable for coating agglomerated particles from a processing point of view, as well as for achieving good taste masking and adequate drug release times. Such a coating composition, when applied in the form of a melt, has been found to easily cover the surface of agglomerates and to be particularly effective in achieving taste masking.

Coatings based on waxes or lipids generally provide taste masking, but also delay the release of the active ingredient. In contrast, the coated particles of the invention have been found to be taste-masked, but advantageously at the same time capable of providing immediate release of the active ingredient. The particles are therefore especially suitable for use in immediate release pharmaceutical compositions. As defined herein, immediate release, or rapid dissolution, means a dissolution profile in which at least 75% of the active ingredient dissolves within 45 minutes, as determined by the use of an apparatus. dissolution of USP type 2 (paddle apparatus) in 900 mL of an aqueous medium at a pH value where the active ingredient can be soluble and stable at 37 ° C, preferably 0.1 N hydrochloric acid, and at a stirring speed of 100 rpm. The term "immediate release" can be used synonymously with the terms rapid release, rapid dissolution, or the like, as opposed to modified, slow, prolonged, controlled, or sustained release.

The coated particles can have a dissolution profile in which at least 75% of the active ingredient dissolves in 30 minutes, or at least 85% in 30 minutes, or at least 85% in 15 minutes, which also depends of the properties (eg intrinsic solubility) of the active ingredient.

As mentioned above, solid at room temperature means that the lower limit of the triglyceride melting range is greater than about 20 ° C. More preferably, the lower limit of the triglyceride melting range is greater than about 35 ° C. In other preferred embodiments, the melting range is from about 40 ° C to about 85 ° C, or from about 45 ° C to about 70 ° C. If more than one triglyceride is present in the coating, at least one of them, representing a significant fraction of the total triglyceride content in the coating, should have a melting range according to one of these preferences. Melting ranges are understood to be provided, as usual, for normal atmospheric pressure, e.g. ex. approximately 1013 mbar.

In particular, native triglycerides often comprise fatty acid residues with different chain lengths and degrees of saturation, that is, they represent mixtures of various chemically different triglycerides. Therefore, in order to achieve more reproducible properties, triglycerides are sometimes purified or manufactured semi-synthetically. Such more defined grades of triglycerides are also preferred according to the invention.

According to one of the preferred options, the triglyceride is a substantially pure triglyceride, having a chemical purity of at least about 90%, that is, it comprises only a small fraction of triglycerides with fatty acid residues other than the main fraction. In particular, the chemical purity of the triglyceride can be at least about 95%, or at least about 97%, respectively.

According to another preferred option, the triglyceride is substantially saturated. In particular, the iodine value, which is a parameter commonly used to describe the degree of unsaturation of triglycerides and which reflects the mass of iodine in grams consumed per 100 grams of a triglyceride, can be less than about 10, or not greater than about 5, or not greater than about 2, or not greater than about 1, respectively.

According to a more preferable option, the fatty acid residues of the triglyceride are substantially the same, that is, at least about 80%, or at least about 90%, or even at least about 95% of the acyl chains have the same number of carbon atoms and degree of saturation. Saturated triglycerides having acyl residues of 10 to 30 carbon atoms are especially useful. Saturated triglycerides having acyl residues with a chain length of 14 to 22 carbon atoms are also preferred. Coatings comprising a triglyceride comprising at least one acyl chain having 16 to 18 carbon atoms are especially preferred.

Furthermore, the triglyceride can be selected from trimyristin (also known as glyceryl trimyristate, m.p. approx.

56-57 ° C), Tripalmitin (also known as Glyceryl Tripalmitate, mp 61-65 ° C), Tristearin (also known as Glyceryl Tristearate, mp 70-73 ° C), Triarachidine (also known as Triarachidate glyceryl, mp approx. 76-80 ° C) and tribehenin (glyceryl tribehenate, mp approx. 82-86 ° C), respectively, especially from tripalmitin and tristearin. In a preferred embodiment, the triglyceride in the coating is selected from glyceryl tripalmitate and glyceryl tristearate. Optionally, two or more of these triglycerides can be used in combination.

Tripalmitin and tristearin, like many other saturated triglycerides, exhibit polymorphism. These triglycerides have an amorphous form and various crystalline forms, that is, an unstable a-modification, a metastable p 'modification, and a thermodynamically stable p-modification. Tripalmitin (in its stable p-form) generally has a melting range, as determined by DSC, of 61 to 65 ° C, while the melting range of tristearin is around 70 to 73 ° C.

Apart from the triglyceride, the coating comprises a surfactant, specifically a polysorbate. The inventors have surprisingly discovered that coating compositions comprising certain surfactants in combination with a solid triglyceride, in particular nonionic surfactants such as polysorbates, can be applied as hot melt coatings at relatively low temperatures, leading to coated particles they do not undergo any major change with respect to their drug release behavior. Thus, the invention allows the coating of temperature sensitive drugs while achieving a product with significantly improved physical stability.

This is in sharp contrast to the teachings of the prior art, according to which the use of triglycerides as hot melt coating materials is discouraged because the polymorphism of the triglyceride leads to dissolution profiles that change over time. Without wishing to be bound by theory, the inventors presently believe that the content of surfactant in the coating composition leads to an induction of thermodynamically stable p-modification of the triglyceride at moderate temperatures, that is, substantially below the recrystallization temperature of the triglyceride. , so that the modification p is already formed at the moment in which the coating composition, applied to the core in the form of a hot melt, solidifies while cooling, or shortly thereafter, that is, in minutes or a few hours maximum. Without the surfactant content, the stable p-modification of tristearin, for example, would only be obtained at a temperature close to 60 ° C, and such a temperature would be detrimental to thermolabile compounds.

In other cases, it may also be possible for the surfactant to stabilize the a-form of the triglyceride. In both cases, the consequence is that no polymorph conversion takes place during storage, and therefore no physical change takes place in the coating with a potential impact on the dissolution profile of the drug.

The coating does not comprise any additional lipid or waxy components other than the triglyceride described above. In particular, the coating may be free of higher melting components that require increased processing temperatures or that could lead to spray nozzle clogging, such as carnauba wax.

As mentioned above, the surfactant in the coating is a nonionic surfactant, specifically a polysorbate. In particular, polysorbates, such as polysorbate 65, have been found to be very suitable in combination with tristearin and trypalmitin. Optionally, two or more polysorbates can be used in combination.

The surfactant, in particular the non-ionic surfactant, and specifically the polysorbate has a hydrophilic-lipophilic equilibrium (HLB) value in a medium range, in particular from about 5 to about 15, as described by Griffin (Calculation of HLB Values of Non-Ionic Surfactants, Journal of the Society of Cosmetic Chemists 5 (4): 249-56, 1954). Also preferred is a nonionic surfactant, and specifically a polysorbate, with an HLB value in the range of about 6 to about 14, or about 7 to about 13, or about 8 to about 12. , respectively. For example, polysorbate 65 exhibits an HLB value of around 10.5, and polysorbate 85 has an HLB value of around 11.

To achieve a pronounced stabilizing effect on the triglyceride of the coating, it is recommended to incorporate the surfactant, specifically the polysorbate, at a surfactant / triglyceride ratio of at least about 0.05. More preferably, the ratio is in the range of about 0.05 to about 0.5, such as about 0.1,0,15, 0.2, 0.25, 0.3, 0.35, 0.4, or 0.45. The coating composition can basically consist of about 50 to 95% by weight of triglyceride and of about 5 to 50% by weight of surfactant, specifically polysorbate, in particular of about 70 to 95% by weight of triglyceride and from about 5 to 30% by weight of surfactant, specifically polysorbate.

Preferably, the surfactant dissolves in, or is miscible with, the triglyceride in the molten state, that is, the surfactant is not incorporated at a level that results in the formation of an emulsion or suspension in the molten state in which it is applied. the coating composition to the core particle. In this way, there is little risk of the coating composition comprising the surfactant and triglyceride separating into two phases at any time during or after the coating process, and a reduced risk of nozzle clogging during the coating process. , as in the case of a suspension.

The coating is free of other constituents, so that the coating basically consists of a triglyceride and a polysorbate surfactant. In fact, one of the preferred coating compositions consists basically of about 70% by weight of tristearate and about 30% by weight of polysorbate 65. Another preferred coating composition consists basically of about 90% by weight of tripalmitin and about 10% by weight of polysorbate 65. The application of one of these coating compositions, for example a coating composition comprising 70 to 90% by weight of triglyceride and 10 to 30% by weight of polysorbate, to agglomerated particles of active ingredient in the form of a hot melt is surprisingly effective in simultaneously achieving effective taste masking as well as rapid drug release, without changes in release profile during storage. This is especially true when the active ingredient is ibuprofen, ibuprofen sodium, or ibuprofen potassium.

The thickness of the cladding is selected taking into account the size and shape of the core. For example, if flake or needle-shaped core particles are to be taste masked, this may require applying a larger relative amount of coating composition than in the case of substantially spherical core particles having the same surface area. . The skilled person will appreciate that different cladding to core weight ratios are necessary for different sizes of cores to obtain the same cladding thickness.

For the coating of typical, somewhat irregularly shaped agglomerated active ingredient particles having a mass average particle size, as determined by sieve analysis, in the range of about 100 to about 1000 pm, the ranges Useful amounts of coating composition required to achieve taste masking are about 20 to 70% by weight, or about 30 to 50% by weight, or about 40 to 60% by weight, or about 50 to 70% by weight relative to the total weight of the coated particle. This is especially advantageous in the case where the active ingredient is ibuprofen, ibuprofen sodium or ibuprofen potassium.

In one especially useful embodiment that simultaneously achieves effective taste masking, rapid dissolution or immediate drug release, and a stable dissolution profile, the core particles of the agglomerated active ingredient, such as ibuprofen or ibuprofen sodium or potassium , having a mass average particle size of about 100 to about 1000 pm are coated with a coating consisting basically of 70% by weight of tristearin and about 30% by weight of polysorbate 65, wherein the coating it is applied in the form of a hot melt on the core particles in an amount of about 30 to 60% by weight, such as 50% by weight, based on the weight of the coated particles. In another especially useful embodiment, the same core particles are coated with a coating consisting basically of 90% by weight of tripalmitin and about 10% by weight of polysorbate 65, wherein the Coating is applied in the form of a hot melt on the core particles in an amount of about 20 to 50% by weight, such as 30% by weight, based on the weight of the coated particles.

The coated particle according to the invention, specifically the immediate release particle, can be manufactured by various methods, including coating of core particles by conventional solvent-based coating methods, in which the coating composition is dissolved in an organic solvent and is subsequently sprayed onto the core particles under conditions whereby the solvent is evaporated.

More preferably, however, the coating composition is melted and sprayed as a hot melt onto the core particles. In this way, the use of an organic solvent and the associated negative environmental, health and safety risks can be avoided. Therefore, the invention provides a method for the preparation of the coated particle described above, comprising the steps of (a) providing a core particle comprising at least 10% by weight of an agglomerated active ingredient relative to the weight of the core, (b) providing a coating composition consisting basically of 70 to 90% by weight of a molten triglyceride and 10 to 30% by weight of a surfactant, specifically a polysorbate, and (c) coating the particle of core with the coating composition, wherein the coating is 20 to 70% by weight with respect to the total weight of the coated particle. In the most preferred embodiments, the core comprises at least about 30% by weight of the active ingredient, or at least about 50% by weight, or at least about 60% by weight, or at least about 70% by weight. , or at least about 80% by weight, or at least about 90% by weight, or at least about 95% by weight, or even at least about 98% by weight of the active ingredient, respectively. One of the preferred active ingredients in this context is ibuprofen, ibuprofen sodium or ibuprofen potassium.

In another preferred embodiment, the invention provides a method for the preparation of the coated particle described above, comprising the steps of (a) providing a core particle comprising at least 10% by weight of an agglomerated active ingredient relative to weight of the core, (b) providing a coating composition consisting basically of 70 to 90% by weight of a molten triglyceride and 10 to 30% by weight of a polysorbate, and (c) coating the core particle with the composition coating, where the weight of the coating is 20 to 70% by weight with respect to the total weight of the coated particle, and where the triglyceride is a material that is solid at room temperature (20-25 ° C), or, in other words, a triglyceride whose lower limit of the melting range is greater than 20 ° C, and wherein the core particle has a sieve diameter in the range of about 100 pm to about 1,000 pm.

The method can be carried out on any suitable coating equipment, the precise configuration of which is selected in particular taking into account the particle size of the core material. For example, the method can be carried out in a fluidized bed coater or in an air flow bed coater.

One of the particular advantages of the invention is that the coating composition and the process of the invention provide an effective means for coating the agglomerated particles of active ingredient. The agglomerated particles of the active ingredients generally have a low mechanical stability and are not easily processed, that is, they cannot be easily coated since the mechanical, as well as thermal, stress involved in most coating processes would lead to reduction or disintegration of the agglomerate.

This generally results in substantially reduced coating efficiency, and also in the generation of an undesirable powder of active ingredient. Active ingredient powder can make coating equipment and coating process difficult. Disintegration of the agglomerate during the coating process can lead to unacceptable inconsistencies in the active ingredient content of the coated particles. Furthermore, in some cases, additional agglomerates formed between the agglomerated active ingredient core and the coating mixture may result, rather than an actual coating layer.

The coating composition and method of the invention have been found to overcome such problems. Efficient coating is achieved and no agglomeration with the coating material is observed when cores comprising an agglomerated active ingredient, specifically cores comprising at least 10% by weight of an agglomerated active ingredient, are sprayed with the composition of coating comprising a triglyceride that is solid at room temperature and a surfactant, specifically a polysorbate. No substantial disintegration of the agglomerated cores of active ingredient is observed. Importantly, the resulting coated particles are found to have an effectively masked taste, and at the same time have fast dissolution profiles.

This is especially true for compounds where the taste is difficult to mask, such as ibuprofen sodium.

Another advantage of the invention is that the coating composition allows processing at fairly low temperatures, and is therefore especially suitable for the processing of drug substances that are sensitive to degradation at high temperatures. In general, it is not very suitable to coat thermally labile active ingredients with hot melt coating compositions that require a high coating temperature, such as coating compositions based on carnauba wax or other waxes.

Preferably, the temperature of the product during the coating process is kept below about 60 ° C, in particular below about 55 ° C. According to a further preference, the product temperature is maintained between about 20 and 50 ° C while the coating composition is applied to the core particles in the form of a melt. In this regard, the nature of the triglyceride of the coating should also be taken into account: In the case of a coating composition based on a lower melting triglyceride, such as tripalmitin, the product temperature can be kept between about 20 and 35 ° C, while in the case of a coating composition based on a higher melting triglyceride, such as tristearin, the product temperature can be maintained between about 20 and 50 ° C, in particular between about 35 and 50 ° C, such as between about 40 and 48 ° C. Especially preferred is the method of preparing a coated particle according to the invention, which involves maintaining the temperature of the product between 20 and 50 ° C while carrying out step (c) of the method, and / or where step (c ) is carried out in a fluidized bed coater or an air flow bed coater.

In a further aspect, the invention provides a pharmaceutical composition comprising the coated particle described above. Coated particles as described herein are especially suitable for incorporation into a composition for oral administration, particularly in the form of granules, such as dispersible granules, effervescent granules, direct-to-mouth granules, or in the form of a tablet. , such as a dispersible tablet, an effervescent tablet, or an orally disintegrating tablet.

Especially useful embodiments are oral formulations that consist of multiple units, or that disintegrate in the patient's mouth into multiple units, such as direct-to-mouth granules or an orally disintegrating tablet, because for these types of formulations the effect of masking The taste of multiple units is crucial to patient acceptance.

As used herein, direct-to-mouth granules are oral compositions designed to direct oral administration without water. The direct-to-mouth granules can represent mixtures of various types of multiple units, which units can be agglomerated and / or non-agglomerated particles. Often such direct-to-mouth granule compositions represent mixtures of sweetening agents, such as carbohydrates or carbohydrate alcohols, flavors, and the drug, any of which may be agglomerated or granulated.

An orally disintegrating tablet can be defined as solid unit dosage forms that rapidly disintegrate in the patient's mouth without chewing, generally in less than about one or two minutes. Orally disintegrating tablets are typically compressed with lower compression forces than conventional tablets, to obtain greater porosity. Alternatively, its porosity can be increased by a drying or sublimation step for those tablets that contain a high amount of moisture or a sublimable excipient. With regard to its formulation, the optimized use of disintegrants, such as commonly used cross-linked polymers, celluloses with low degree of substitution, or effervescent partners, further contribute to the rapid disintegration. Also popular is the use of highly water-soluble excipients that allow the actual dissolution of important parts of the formulations in saliva, and that provide a smoother mouthfeel compared to other formulations that disintegrate quickly, but leave mostly residue. insoluble parts.

Additional embodiments, options, and / or preferences are illustrated by the following examples.

Examples

Example 1: Compacted Ibuprofen Sodium Hot Melt Coating

Ibuprofen sodium dihydrate (66.5% by weight) having a median particle size of 77.6 pm and Avicel PH 105 (33.5% by weight) were roller compacted (batch size 1000g to 2000g) by the use of a WP 120 Pharma type roller compactor (Alexanderwerk) at a roller speed of 3.5 rpm and a feed screw speed of 80 rpm. The hydraulic pressure was 60 bar and sieves with mesh sizes of 0.8 mm (Sample 1B) or 1.25 mm (Sample 1A) were used to form the granules. The granules were then sieved (355 pm mesh size) to obtain granules having a sieve diameter above 355 pm.

The resulting granules (cores) were fluidized in a laboratory scale air flow bed coater (Ventilus V-1, Innojet Herbert Huettlin, Steinen, Germany) and kept at a temperature of 28-30 ° C. A molten coating mixture of 90% by weight of tripalmitin (Dynasan 116) and 10% by weight of polysorbate 65 (Tween 65) was stirred at a temperature of 100 ° C. The molten coating composition was then sprayed onto the ibuprofen sodium dihydrate granules at a spray rate of 6.4-7.1 g / min with an atomization pressure of 0.8 bar until the desired amount of coating was achieved. . It was confirmed by visual inspection that the core granules were not further agglomerated, but coated with the coating composition. Coated granule samples comprising 30-35% by weight of coating material (see Samples 1A and 1B) relative to their total weight were prepared in this manner.

Subsequently, the coated granules were tested for taste and dissolution behavior. The Dissolution test was carried out on a shovel apparatus (USP). 400 mg of the coated granules were placed in dissolution vessels filled with 900 mL of dissolution buffer at pH 6.8 and stirred at 100 rpm at 37 ° C. Ibuprofen sodium dihydrate content was analyzed by an established HPLC method (according to the European Pharmacopoeia). A panel of experts evaluated taste masking using a subjective organoleptic taste test. Water (1 mL) was injected into the oral cavity of a participant before taking a sample. An amount of coated particles equivalent to a 400 mg dose of ibuprofen sodium dihydrate was used for the taste test. The time before the participant had a soapy or unpleasant taste sensation was recorded.

Coating Sample (% in Drug Solution Taste Test

weight)

1A 30 85% in 30 min> 50 s

1B 35 85% in 30 min> 50 s

Example 2: Compacted Paracetamol Hot Melt Coating

Paracetamol (70% by weight) and Avicel PH 105 (30% by weight) were compacted with rollers (batch size 1700 g; roller compactor: Alexanderwerk WP 120 Pharma) at a roller speed of 5 rpm, a screw speed 35 rpm feed and a hydraulic pressure of 170 bar. A 1.25mm mesh size screen was used to form the granules.

The resulting granules (cores) were fluidized in a laboratory scale air flow bed coater (Ventilus V-1, Innojet Herbert Huettlin, Steinen, Germany) and kept at a temperature of 25-32 ° C. A molten coating mixture of 90% by weight of tripalmitin (Dynasan 116) and 10% by weight of polysorbate 65 (Tween 65) was stirred at a temperature of 100 ° C. The molten coating composition was then sprayed onto the paracetamol / acetaminophen granules at a spray rate of 8.1 g / min with an atomization pressure of 0.8 bar until an amount of 40% by weight of coating was achieved. , relative to the total weight of the coated granule. It was confirmed by visual inspection that the core granules were not agglomerated, but coated with the coating composition.

Subsequently, the coated granules were tested for taste and dissolution behavior. The dissolution test was carried out on a paddle apparatus (USP). 1000 mg of the coated granules were placed in dissolution vessels filled with 900 mL of 0.1 N HCl and stirred at 100 rpm at 37 ° C. The paracetamol content was analyzed by an established HPLC method (according to the European Pharmacopoeia). A panel of experts evaluated taste masking using a subjective organoleptic taste test. Water (1 mL) was injected into the oral cavity of a participant before taking a sample. An amount of coated particles equivalent to a 400 mg dose of paracetamol was used for the taste test. The time before the participant had a bitter or unpleasant taste sensation was recorded.

As a result, it was found that the coated granules released 85% of the active ingredient in 30 minutes. The taste was found to be acceptable as no bitter or unpleasant taste could be detected in 65 s, ie the coating provided effective taste masking.

Example 3: Granulated Calcium Acetate Hot Melt Coating

The calcium acetate granules (cores) were fluidized in a laboratory scale air flow bed coater (Ventilus V-1, Innojet Herbert Huettlin, Steinen, Germany) and kept at a temperature of 25-32 ° C. A molten coating mixture of 90% by weight of tripalmitin (Dynasan 116) and 10% by weight of polysorbate 65 (Tween 65) was stirred at a temperature of 100 ° C. The molten coating composition was then sprayed onto the calcium acetate granules at a spray rate of 6.5 g / min with an atomization pressure of 0.8 bar until a coating amount of 30% by weight was achieved, relative to the total weight of the coated granule. It was confirmed by visual inspection that the core granules were not agglomerated, but coated with the coating composition.

The coated granules were tested for their dissolution behavior. The dissolution test was carried out on a paddle apparatus (USP). 100 mg of the coated granules were placed in dissolution vessels filled with 900 mL of buffer at pH 1.2 and stirred at 50 rpm at 37 ° C. The calcium acetate content was analyzed by an established EAA method. As a result, 94% of the calcium acetate was released in 10 minutes.

Example 4: Granulated Caffeine Hot Melt Coating

The caffeine granules (nuclei) were fluidized in a laboratory scale air flow bed coater (Ventilus V-1, Innojet Herbert Huettlin, Steinen, Germany) and kept at a temperature of 25-53 ° C. A molten coating mixture of 90% by weight of tripalmitin (Dynasan 116) and 10% by weight of polysorbate 65 (Tween 65) was stirred at a temperature of 100 ° C. The molten coating composition was then sprayed onto the caffeine granules at a spraying speed of 6.5 g / min with an atomization pressure of 0.8 bar until an amount of 30% by weight of coating was achieved, relative to the total weight of the coated granule. It was confirmed by visual inspection that the core granules were not agglomerated, but coated with the coating composition.

The coated granules were tested for their dissolution behavior, directly after manufacture and during storage. The dissolution test was carried out on a paddle apparatus (USP). 100 mg of the coated granules were placed in dissolution vessels filled with 500 mL of 0.1 N HCl and stirred at 100 rpm at 37 ° C. Caffeine content was analyzed by an established HPLC method (according to the European Pharmacopoeia).

Storage Dissolution

Initial> 80% in 20 min

25 ° C / 60% r.h. 3 months> 80% in 20 min

40 ° C / 75% r.h. 1 month> 80% in 20 min

40 ° C / 75% r.h. 3 months> 80% in 20 min

Example 5: Granulated Ibuprofen Hot Melt Coating

The DC 100 agglomerated ibuprofen granules (cores) having a median particle size of 308 pm were fluidized in a laboratory scale air flow bed coater (Ventilus V-1, Innojet Herbert Huettlin, Steinen, Germany) and they were kept at a temperature of 25-32 ° C. A molten coating mixture of 86% by weight of tripalmitin (Dynasan 116) and 14% by weight of polysorbate 65 (Tween 65) was stirred at a temperature of 100 ° C. The molten coating composition was then sprayed onto the ibuprofen granules at a spray rate of 6.4-7.1 g / min with an atomization pressure of 0.8-1 bar until 30% by weight was obtained. of coating material relative to the total weight of the coated granules. It was confirmed by visual inspection that the core granules were not further agglomerated, but coated with the coating composition.

Example 6: Preparation of direct-to-mouth ibuprofen granules

Direct-to-mouth granules were prepared by combining the coated granules of Example 5 with the following excipients:

Component mg / Dose

Coated ibuprofen from Example 5 (70% by weight ibuprofen) 571.43

Sorbitol 548.57

Xylitol 290.00

Citric acid 12.00

Monosodium citrate 20.00

Magnesium citrate 30.00 Sodium carboxymethylcellulose 15.00

Aspartame 1.00

Mint aroma 1.50

Cherry aroma 8.50

Magnesium stearate 2.00

Claims (14)

1. An immediate release particle comprising a core and a coating, wherein the core comprises an agglomerated active ingredient in an amount of at least 10% by weight relative to the weight of the core, and wherein the coating basically consists of the 70 to 90% by weight of a triglyceride and 10 to 30% by weight of a polysorbate, and where the lower limit of the melting range of the triglyceride is greater than 20 ° C, and where the weight of the coating is 20 70% by weight relative to the total weight of the coated particle. 2. The particle of claim 1, wherein the triglyceride comprises at least one acyl chain having 16 to 18 carbon atoms, and is preferably selected from trypalmitin and tristearin. 3. The particle of claim 1, wherein the polysorbate is polysorbate 65. 4. The particle of any preceding claim, wherein the core has a diameter in the range of 100 µm to 1,000 µm. The particle of any preceding claim, wherein the active ingredient is selected from analgesics, non-steroidal anti-inflammatory drugs, proton pump inhibitors, antitussives, antihistamines, stimulants, sedatives, decongestants, antiemetics, phosphate binding agents, and sympathomimetics. 6. The particle of any preceding claim, wherein the active ingredient is selected from ibuprofen, paracetamol, caffeine, calcium acetate, aspirin, pseudoephedrine, dimenhydrinate, omeprazole, pantoprazole, or lansoprazole, or any of its salts, isomers, polymorphs, and hydrates. 7. The particle of any preceding claim, wherein the active ingredient is agglomerated ibuprofen or ibuprofen sodium salt or ibuprofen potassium salt. 8. The particle of any preceding claim, wherein the coating consists basically of 90% by weight of tripalmitin and 10% by weight of polysorbate 65; or wherein the coating consists basically of 70% by weight of tristearin and 30% by weight of polysorbate 65. 9. The particle of any preceding claim, wherein the core consists substantially of the agglomerated active ingredient. 10. The particle of any preceding claim, wherein the particle can be obtained by a method comprising the steps of (a) providing a core particle comprising an agglomerated active ingredient in an amount of at least 10% by weight relative to the weight of the core, (b) providing a coating composition consisting basically of 70 to 90% by weight of a molten triglyceride and 10 to 30% by weight of a polysorbate, wherein the lower limit of the melting range of the triglyceride is greater than 20 ° C, and (c) coating the core particle with the coating composition, wherein the weight of the coating is 20 to 70% by weight relative to the total weight of the coated particle. 11. A pharmaceutical composition comprising the particle of any one of claims 1 to 10. The pharmaceutical composition of claim 11, which is formulated in the form of granules, such as dispersible granules, effervescent granules, direct-to-mouth granules, or in the form of a tablet, such as a dispersible tablet, an effervescent tablet, or an orally disintegrating tablet. 13. A method for the preparation of the particle of any one of claims 1 to 10, comprising the steps of (a) providing a core particle comprising at least 10% by weight of an agglomerated active ingredient relative to the weight of the core, (b) providing a coating composition consisting basically of 70 to 90% by weight of a molten triglyceride and 10 to 30% by weight of a polysorbate, and (c) coating the core particle with the coating composition, wherein the weight of the coating is 20 to 70% by weight relative to the total weight of the coated particle. The method of claim 13, wherein the product temperature is maintained between about 20 and 50 ° C while step (c) is carried out, and / or where step (c) is carried out in a fluidized bed coater or an air flow bed coater. Ċ